A case-control study of risk factors for multiple sclerosis in Iran.

BACKGROUND: Numerous studies have assessed risk factors for multiple sclerosis (MS), although none have been conducted previously in Iran. OBJECTIVE: The objective of this study was to study lifestyle and environmental risk factors of MS in the Iranian population. METHODS: A case-control study, including 394 MS cases and 394 matched controls, was conducted in MS clinics in different Iranian cities. Information on lifestyles, environmental exposures, and past medical history was obtained from medical charts and phone interviews. RESULTS: In multivariable analysis, sunlight exposure was associated with a lower risk of MS: the odds ratio (OR) and 95% confidence interval (CI) of MS associated with a 1-h increment in daily sunlight was 0.62 (0.53-0.73). Smoking was associated with MS risk in women (OR: 6.48, 95% CI: 1.46-28.78), but not in men (OR: 0.72, 95% CI: 0.31-1.68) (p=0.002 for interaction). Finally, past history of common surgical procedures, infectious disorders, or exposure to pets and farm animals was not associated with MS risk. CONCLUSIONS: Different modifiable lifestyles, including sunlight exposure and smoking, were associated with lower MS risk in Iran. Interventions aimed at promoting smoking cessation and, more importantly, at increasing exposure to sunlight might contribute to the prevention of MS.

Clinical consequences of MRI activity in treated multiple sclerosis.

BACKGROUND: Inflammation on brain MRI is the most sensitive marker of disease activity in multiple sclerosis (MS) but its clinical consequences remain controversial. OBJECTIVE: Here we investigated the clinical consequences of MRI activity in MS subjects treated with two different first line disease modifying agents. METHODS: Seventy-five treatment-naïve subjects with relapsing-remitting MS (N = 61) or clinically isolated syndromes at risk of MS (N = 14) from the BECOME study that had been randomized to interferon beta-1b (N = 39) or glatiramer acetate (N = 36) and followed for up to two years by monthly brain MRI optimized to detect inflammatory activity were studied for the clinical consequences of lack of MRI remission. RESULTS: MRI remission occurred in 46.4% of participants transiently and in 23.2% completely while it was never achieved in 30.4%. There was no difference by treatment in MRI remission, progression of physical disability, or cognitive function. The percentage of relapse-free subjects was 87.5% for the group in complete MRI remission, 47.6% in the group never in remission and 59.4% in the group in transient remission (p = 0.017). Similar differences were observed for six-month-confirmed worsening of ambulatory function as measured by the timed 25 foot walk (p = 0.026) and by Expanded Disability Status Scale (EDSS) (p = 0.10). Cognitive function was lowest at baseline for the group that never reached MRI remission on treatment; this group improved the least upon repeated cognitive testing during the two years of treatment (p < 0.001). CONCLUSIONS: Lack of MRI remission during treatment with interferon beta-1b or glatiramer acetate is associated with higher relapse rate and worsening of physical and cognitive function.

A second case of Marburg's variant of multiple sclerosis with vasculitis and extensive demyelination.

Marburg's variant of multiple sclerosis is a rapidly progressive and malignant form of multiple sclerosis (MS) that usually leads to severe disability or death within weeks to months without remission. Few cases have been described in the literature since the original description by Marburg. The classic pathological findings usually include highly destructive zones of extensive demyelination, necrosis with dense cellular infiltrate, and giant reactive astrocytes. We report a case of a 31-year-old woman with Marburg's variant of MS who, over a period of eight months, became totally disabled, blind, and quadriplegic, with vocal cord paralysis, requiring a tracheostomy. The patient underwent diagnostic stereotactic brain biopsy. Clinical findings, magnetic resonance imaging (MRI), serologic and cerebrospinal fluid (CSF) findings, and neuropathology are discussed. MRI showed extensive white matter involvement in the brain and spinal cord that continuously progressed over time. A diagnostic stereotactic brain biopsy revealed extensive active demyelination with unexpected finding of active vasculitis and fibrinoid necrosis with a vascular inflammatory cell infiltrate, including polymorphonuclear neutrophils and rare eosinophils. Serologic work-up for vasculitis and neuromyelitis optica was unremarkable and the CSF showed only one oligoclonal band (OCB) not present in serum. This is the second case of Marburg's variant of MS that demonstrated both demyelination and vasculitis. In our case these features were demonstrated simultaneously, even though the demyelination was the predominant pathological finding. Since vasculitis is not a feature of classic MS, these findings pose the question as to whether Marburg's variant of MS is a true variant or different entity altogether.

Increased frequency of canine distemper virus-specific antibodies in multiple sclerosis.

BACKGROUND AND PURPOSE: Canine distemper virus (CDV) is a candidate agent in the etiology of multiple sclerosis (MS). Elevated anti-CDV levels were previously found in the sera from MS patients compared with controls. We now investigated whether there was an age-related association with the presence of antibodies specific to CDV-hemagglutinin (H) protein in MS. METHODS: Sera from patients with MS, other neurological diseases, and inflammatory and/or autoimmune diseases, and healthy individuals were screened for anti-CDV in an ELISA using linear peptides of the CDV-H protein as antigen. Antibody levels to measles and varicella-zoster virus were measured and served as controls. RESULTS: Analysis of the new cohort of MS patients and controls confirmed our initial finding of elevated anti-CDV-H levels in MS patients. An increase in measles but not varicella-zoster virus antibody levels was found in MS patients compared with healthy controls. Data from the new cohort of patients and controls were combined with data from the original study and analyzed with respect to age distribution of anti-CDV IgG. Mean CDV antibody levels were significantly elevated in each decade from 20 to 50 years of age in MS compared with healthy and disease controls. Antibody levels to measles virus were not consistently elevated during this age span. A striking relationship (p < .0001, odds ratio = 5.0) was observed between elevated anti-CDV-H levels and diagnosis of MS. CONCLUSIONS: The finding that anti-CDV levels are elevated in MS patients of all ages provides substantial evidence of a strong association between elevated anti-CDV and MS.

Gray Matter Nucleus Hyperintensity After Monthly Triple-Dose Gadopentetate Dimeglumine With Long-term Magnetic Resonance Imaging.

OBJECTIVES: Gadolinium deposition is widely believed to occur, but questions regarding accumulation pattern and permanence remain. We conducted a retrospective study of intracranial signal changes on monthly triple-dose contrast-enhanced magnetic resonance imaging (MRI) examinations from the previously published Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial (N = 67) to characterize the dynamics of gadolinium deposition in several deep brain nuclei and track persistence versus washout of gadolinium deposition on long-term follow-up (LTFU) examinations (N = 28) obtained approximately 10 years after enrollment in the Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial. MATERIALS AND METHODS: Using T2 and proton density images and using image analysis software (ITK-SNAP), manual regions of interest were created ascribing boundaries of the caudate nucleus, dentate nucleus, globus pallidus, pulvinar, putamen, white matter, and air. Intensity analysis was conducted on T1-weighted fat-saturated (fat-sat) images using the FSL package. A linear rigid-body transform was calculated from the fat-sat image at each target time point to the region of interest segmentation reference time point fat-sat image. Serial MRI signal was analyzed using linear mixed regression modeling with random intercept. Annual MRI signal changes including LTFU scans were assessed with t test. RESULTS: During monthly scanning, all gray matter structures demonstrated a significant (P < 0.0001) increase in contrast-to-noise ratio. Yearly changes in deposition showed distinctive patterns for the specific nucleus: globus pallidus showed complete retention, pulvinar showed partial washout, while dentate, caudate, and putamen returned to baseline (ie, complete washout). CONCLUSIONS: Monthly increased contrast-to-noise ratio in gray matter nuclei is consistent with gadolinium deposition over time. The study also suggests that some deep gray matter nuclei permanently retain gadolinium, whereas others demonstrate washout of soluble gadolinium.

Long-term topical steroid treatment after penetrating keratoplasty in patients with pseudophakic bullous keratopathy.

PURPOSE: To assess the use of long-term topical corticosteroid treatment in patients with pseudophakic bullous keratopathy (PBK) after penetrating keratoplasty (PK). DESIGN: Retrospective cohort study. PARTICIPANTS: This study considered patients with PBK undergoing an initial PK procedure for visual reasons in the United Kingdom between April 1999 and March 2004. There were 1274 initial PK procedures for PBK reported to United Kingdom Transplant in this period, of which 1184 (91%) were grafted for visual reasons. Of these 1184 grafts, follow-up was reported in 1033 instances (87%). METHODS: A Cox regression model was used to investigate the combined effects of all preoperative factors (recipient age, human leukocyte antigen [HLA] matching, trephine size, deep stromal vascularization, surgeon activity) on graft failure. The model was fitted using all preoperative factors first, and subsequently, factors associated with corticosteroid and other medications were included. MAIN OUTCOME MEASURES: Graft survival. RESULTS: Three-year survival of grafts for PBK was 65% (95% confidence interval [CI], 59%-70%). Topical corticosteroids were still being used beyond 18 months after surgery in 378 (37%) of the 1033 corneal grafts included in this study. The grafts of patients not currently receiving steroids were 1.5 times as likely to fail (hazard ratio [HR], 1.5; 95% CI, 1.0-2.2; P<0.03). Lack of HLA matching (P = 0.006), trephine size or=8.00 mm (P = 0.03), recipient age younger than 65 years (P = 0.003), and corneal vascularization (P = 0.04) all increased the risk of graft failure. CONCLUSIONS: The use of long-term postoperative corticosteroids improved graft survival after PK for PBK. Barring patient contraindications for long-term topical corticosteroid use, clinicians should consider maintaining patients with PBK on long-term postoperative corticosteroid maintenance.

Serum levels of CXCL13 are elevated in active multiple sclerosis.

There is increasing recognition of the important role that B cells play in the pathogenesis of multiple sclerosis (MS). Recently it was reported that the B cell chemokine CXCL13 is elevated in MS serum and cerebrospinal fluid. Here we study whether serum levels of CXCL13 are associated with active MS. We measured serum levels of CXCL13 by enzyme-linked immunosorbent assay in 74 patients with relapsing MS randomized to interferon beta 1b or glatiramer acetate and examined with monthly 3 T brain MRI scans optimized for detection of gadolinium-enhancement for up to 2 years. The median (range) serum levels of CXCL13 pre-treatment were 40 (3-171) pg/ml. Serum levels of CXCL13 were significantly higher at times of active brain MRI scans (p < 0.01). Furthermore, serum levels were higher in patients who never reached MRI remission compared with those in complete (p < 0.01) or partial (p = 0.01) remission. There was a significant positive correlation between the pattern of serum levels of CXCL13 and MRI activity during the first (r = 0.33, p < 0.05) and the full 2 years (r = 0.35, p < 0.01) of the study. Treatment with interferon beta 1b or glatiramer acetate did not affect serum CXCL13. We conclude that the serum levels of the B cell chemokine CXCL13 are associated with active MS.

Outcomes of same-sizing versus oversizing donor trephines in keratoconic patients undergoing first penetrating keratoplasty.

PURPOSE: To investigate whether use of same-size donor and recipient trephines reduced myopia after penetrating keratoplasty for keratoconus. DESIGN: Retrospective cohort study. PARTICIPANTS: Eight hundred seventy-eight first grafts for keratoconus were reported to UK Transplant between April 1999 and December 2003. There were 234 and 644 grafts in the same-size and oversize donor trephine groups, respectively. At 1 year, mean spherical equivalent (SE) data were available for 116 eyes (50%) and 295 eyes (46%) in the same-size and oversize groups. At 2 years, mean SE data were available for 64 eyes (27%) and 148 eyes (23%) in the same-size and oversize groups. METHODS: Logistic regression and univariate analysis of follow-up data submitted to UK Transplant. MAIN OUTCOME MEASURES: At 1 and 2 years postoperatively, mean SE, magnitude of the cylindrical component of the refraction, postoperative uncorrected visual acuity (VA), postoperative best-corrected VA, and postoperative complications were recorded. RESULTS: The mean SEs for the same-size and oversize donor trephine groups, respectively, were -1.45 diopters (D) and -1.41 D at 1 year (P = 0.6) and -1.74 D and -2.19 D at 2 years postoperatively (P = 0.3). Although there were no differences in graft survival between the groups at 1 and 2 years, there was a higher incidence of postoperative wound leaks in the same-size group (P = 0.03). CONCLUSION: Use of same-size donor and recipient trephines did not reduce myopia and was associated with an increased risk of postoperative complications.

Could Epstein-Barr virus or canine distemper virus cause multiple sclerosis?

Multiple sclerosis (MS) is thought to be an immune-mediated disease with a possible environmental trigger. Genetic and environmental factors, including infection by pathogens, may act synergistically to trigger the disease. There is growing epidemiologic, serologic, and pathologic evidence that Epstein-Barr virus may cause MS or contribute to its pathogenesis. The evidence that canine distemper virus is involved in MS is less robust. More definitive data are required to prove that Epstein-Barr virus or canine distemper virus causes some or most cases of MS.

Stability of visual outcome between 2 and 5 years following corneal transplantation in the UK.

BACKGROUND AND AIMS: Many studies of corneal transplantation focus on graft failure or rejection as endpoints, or report visual outcomes at one postoperative time point. We aimed to study the stability of visual outcomes between 2 and 5 years following corneal transplantation. METHODS: All patients with keratoconus (868) or Fuchs endothelial dystrophy (FED) (569) receiving their first corneal transplant for visual purposes in the UK between January 2003 and December 2009 were included. The probability of visual improvement or deterioration (gain or loss of ≥2 Snellen lines, respectively) between 2 and 5 years after keratoplasty was modelled by multivariable logistic regression. RESULTS: The majority of keratoconus patients with a penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty maintained their visual acuity (651/868; 75%) while 15% (133/868) improved and 10% (84/868) deteriorated. Similarly, most patients with FED who received a PK maintained their vision (395/569; 70%) while 18% (105/569) improved and 12% (68/569) deteriorated.

Approved drugs and their problems in patient care: routes of administration and dosing.

Problems in patient care with regard to route of administration and dosing of currently approved drugs are reviewed. Dose, frequency and route of administration can make a difference in efficacy, side effects, quality of life, antigenicity, cost, and compliance.

Electrolysis-needle cauterization of corneal vessels in patients with lipid keratopathy.

PURPOSE: To describe a technique of corneal vessel occlusion by using electrolysis-needle cautery. METHODS: A prospective case series of three patients. RESULTS: Corneal vessels were successfully occluded in all patients. Vessels remained occluded during the first 8 months post-cautery follow up. Two patients needed repeat cautery at 9 and 10 months respectively. Patients found the procedure comfortable. There was no post-operative induced astigmatism. CONCLUSION: The technique of ENC is simple, effective and controlled. This technique compares favorably and may prove to be more versatile than Fine Needle Diathermy in the occlusion of corneal vessels that lead to lipid keratopathy.

Multiple sclerosis: pathologic, clinical, and imaging updates.

Highlights of the 21st Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 28-October 1, 2005, Thessaloniki, Greece.

A clinician's approach to modulate disease activity in MS.

All multiple sclerosis (MS) patients should have their treatment profile carefully evaluated as to disease control, optimal therapy, and adverse side effects at every clinical visit, with the goal of safely minimizing disease activity. There is a general consensus among clinicians that therapy should be initiated early in the course of the disease and should be continued indefinitely unless disease activity continues, intolerable side effects develop, patient transitions to a primary progressive course, or more effective and safer drugs become available. Patients for whom treatment is delayed should be seen at least every 6 months, and therapy should be initiated if new disease activity is found. Magnetic resonance imaging is the most practical laboratory test currently available for monitoring ongoing tissue injury and is useful when evaluating the efficacy of a given therapy. Four immunomodulators and 2 immunosuppressants are currently approved for the treatment of relapsing or secondary progressive forms of MS; in addition, various immunosuppressive or immunomodulating drugs have been used off-label, alone or in combination, in clinical practice. Many issues remain to be resolved in attempting to modulate disease activity in MS patients. Consequently, the art of medicine and clinical judgment become important aspects of MS patient care.

Aggressive central nervous system demyelination in an adolescent.

A 15-year-old boy diagnosed with a severe, active, and aggressive form of multiple sclerosis (MS) failed conventional, evidence-based therapy. The optimal treatment of the child or adolescent failing federally approved therapy for MS is unclear, similar to the situation in adults. This case history demonstrates that aggressive immunosuppression might be of at least short-term value in controlling disease acutely in an adolescent, as in adults with MS, when evidence-based therapies do not provide an adequate response.

Long-Term Outcomes of High-Risk Keratoplasty in Patients Receiving Systemic Immunosuppression.

PURPOSE: Immunological graft rejection after corneal transplantation remains the leading cause of graft failure. Systemic immunosuppression is used for keratoplasty at a high risk of rejection to improve graft survival. We examined the long-term outcomes of high-risk corneal grafts in patients receiving systemic immunosuppression. METHODS: Thirty-five corneal transplants with a high risk of rejection were identified from 29 patients within a regional immunosuppression service in the United Kingdom. Definition of keratoplasty at "high risk" of rejection included one or more of the following: a history of ipsilateral graft rejection and/or failure, 2 or more quadrants of stromal vascularization, perforation or ocular inflammation at the time of surgery, presence of atopy, and a large-diameter (≥9 mm) graft. Median follow-up duration was 5 years after transplantation. RESULTS: Graft survival at 5 years in patients receiving systemic immunosuppression was 73.5%. Rejection episodes occurred in 14 grafts (40%); these episodes were reversible in 10 grafts (71%). Indications for transplantation were mostly visual (n = 19; 54%) and tectonic (n = 14; 40%). Eighteen grafts (51%) had 2 or more high-risk characteristics. Most patients (n = 20; 69%) received monotherapy, commonly with tacrolimus (n = 15; 52%) or mycophenolate mofetil (n = 8; 28%). Three patients (10%) experienced severe systemic side effects. Median "day-to-day" logMAR visual acuity was 0.5 in grafts for all indications and 0.2 for visual indications. CONCLUSIONS: Systemic immunosuppression in patients with high-risk keratoplasty seems to improve graft survival with a median follow-up duration of 5 years and is tolerated by most patients. Despite rejection episodes occurring in 40% of grafts, these were mostly reversible.

Hypophosphatemia is Associated with the Serial Administration of Triple-Dose Gadolinium to Patients for Brain MRI.

BACKGROUND AND PURPOSE: The purpose of this study is to report a metabolic abnormality associated with frequent, triple-dose Gadolinium (TdGd) use in MS patients during BECOME trial. METHODS: Potential clinical adverse events and lab abnormalities were monitored at each monthly MRI visit. Hypophosphatemia was defined as phosphate <2.5 mg/dL. Statistical analysis included McNemar's test for pairwise comparisons across visits and generalized estimating equations (GEE) to fit models over time. RESULTS: Eight hundred seventy seven phosphate values were analyzed from the first 12 months. Compared with 4% of subjects at screening, an average of 15.1% (95% confidence interval (CI): 11.4%-19.7%) of patients had hypophosphatemia at visits from months 1 to 12, during which subjects received serial TdGd. Forty four of seventy five (59%) patients developed hypophosphatemia at least once. We also found a significant increasing trend in hypophosphatemia by visit when treatment groups were evaluated together or separately (p < .001). There was a statistically significant decrease in frequency to 9.8% (95% CI: 4.6-19.8%) by month 24 (p = .005) coinciding with a period of less frequent gadolinium administration. CONCLUSIONS: Serial TdGd in MS patients, unrelated to immunomodulatory treatment, was associated with increased frequency of hypophosphatemia that progressed with cumulative triple-dose and markedly decreased in second year, with less frequent triple-dose administration.